In the past few years, extensive efforts have been made toward the development of implantable prostheses and bedside equipment which could continuously control the insulin infusion rate to maintain an appropriate blood glucose level for the patient [1-4]. These devices are called the artificial pancreas or artificial Beta-cell.
The major components required for a system of complete metabolic control are: an insulin infusion pump; an accurate, selective and continuous glucose concentration sensing element; and a logic control device. Several pumps for open-loop programmed insulin infusion have been developed and are now under clinical evaluation. Microminiature, solid state microprocessor computer devices are available or developable as being within the state of the art.
However, a glucose-selective, long-term, and reproducible detector essential for an implantable sensing element has not been available. The development of such a sensor would constitute a breakthrough for both the clinical practice and basic investigation of diabetes and its associated complications. Its absence is the missing link for workable closed-loop insulin infusion systems.
Uses for such a detector would include benchtop analyses, bedside monitoring, and the implanted "artificial pancreas." Significant effects of improved metabolic control on the incidence of complications in diabetes millitus will not be seen until an implantable, closed-loop insulin infusion system with near physiologic performance is available.
Several approaches to the development of an implantable glucose sensor have been explored. These include (1) electrochemical sensors such as those employing amperometric and potentiometric detectors [5-14, 25-27]; (2) enzyme sensors with enzyme coupled to an electrochemical detector [15-22]; and (3) optical sensors [8]. The main difficulties encountered in the development of the conventional electrochemical sensors are twofold: (1) insufficient selectivity for glucose; and (2) poor reproducibility. Lack of reproducibility means the sensor is neither continuous nor reliable, even in intermittant operation. Enzyme sensors suffer from the loss of enzyme activity due to "poisoning" and poor long-term stability. The optical methods are limited by the fact that only minimal optical rotation of the plane of polarization is observed for glucose levels of less than 400 mg/dl [8]. But it is in this vital range (below 400 mg/dl) that medical interest resides. In fact the body ordinarily operates in the much narrower range of 70-150 mg/dl.
Recently, an implantable electrochemical glucose sensor based on a potentiodynamic approach has been studied [11-13, 23]. Though the sensing is relatively reproducible in a glucose solution, it suffers greatly by the inhibition of added co-reactants such as amino acids and urea [9, 11-13, 24-27]. A "compensated net charge method" of signal analysis has been proposed to counter this interference. Preliminary experiments have been reported in which the compensated net charge approach provided some improvement in both sensitivity to glucose and insensitivity to interfering co-reactants [23].
Electrochemical detection could be an answer to glucose (and other carbohydrate) monitoring provided that the sensor is glucose-selective, sensitive, and reproducible (reliable and continuously operating). Moreover, the detecting electrode itself or associated components must not dissolve into body fluid and no toxic substances should be generated. The detector should be susceptible to miniaturization, and provide a sufficient output that can be processed and/or enhanced to be utilized by a controlled infusion system.
The present invention satisfies this unfilled need in the art by providing a carbohydrate sensor that operates by pulsed voltammetry or pulsed coulommetry in the far negative potential range (-0.90 V to -0.20 V) to detect two well defined, distinctly separated, sharp oxidation and reduction (redox) peaks of a reversible simple oxidation-reduction (redox) couple involving a direct, single electron transfer process under diffusion control that is not interfered-with by other oxidizable compounds present in the fluids. The signal exhibits a linear relationship with respect to concentration in the useful physiologic glucose concentration range of 50-400 mg/dl, the voltages of which signals do not shift with changes in glucose concentration, thus permitting continuous, highly selective, reproducible, reliable concentration sensing.